Variant chr10-133127325-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001083909.3(ADGRA1):c.494C>T(p.Thr165Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,592,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ADGRA1
NM_001083909.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

Variant links:

Genes affected

ADGRA1 (HGNC:13838): (adhesion G protein-coupled receptor A1) This gene encodes a protein that belongs to the adhesion family of G-protein-coupled receptors. Members of this family function in several sensory systems and regulate blood pressure, immune responses, food intake and development. A similar protein in rodents is thought to play a role in in the regulation of neuronal signaling pathways. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Mar 2014]

ADGRA1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0691677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA1	NM_001083909.3 linkuse as main transcript	c.494C>T	p.Thr165Met	missense_variant	6/7	ENST00000392607.8	NP_001077378.1	Q86SQ6-3
ADGRA1	XM_011540273.1 linkuse as main transcript	c.-14C>T		5_prime_UTR_premature_start_codon_gain_variant	2/3		XP_011538575.1
ADGRA1	NM_001291085.2 linkuse as main transcript	c.203C>T	p.Thr68Met	missense_variant	3/4		NP_001278014.1	Q86SQ6-2
ADGRA1	XM_011540273.1 linkuse as main transcript	c.-14C>T		5_prime_UTR_variant	2/3		XP_011538575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA1	ENST00000392607.8 linkuse as main transcript	c.494C>T	p.Thr165Met	missense_variant	6/7	5	NM_001083909.3	ENSP00000376384.3		Q86SQ6-3
ADGRA1	ENST00000392606.2 linkuse as main transcript	c.203C>T	p.Thr68Met	missense_variant	3/4	1		ENSP00000376383.2		Q86SQ6-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1440250

Hom.:

Cov.:

AF XY:

0.00000838

AC XY:

AN XY:

716036

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.0000482

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.000106

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000840

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.494C>T (p.T165M) alteration is located in exon 6 (coding exon 5) of the ADGRA1 gene. This alteration results from a C to T substitution at nucleotide position 494, causing the threonine (T) at amino acid position 165 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.075

.;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.30

T;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.069

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.2

.;N;.

REVEL

Benign

0.058

Sift

Uncertain

0.0040

.;D;.

Sift4G

Uncertain

0.046

D;D;D

Polyphen

0.88

P;P;.

Vest4

0.22

MutPred

0.52

.;Gain of catalytic residue at T165 (P = 0.007);.;

MVP

0.043

MPC

0.47

ClinPred

0.27

GERP RS

1.6

Varity_R

0.047

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over